乌鸦传媒

Talazoparib (Talzenna) failed to improve overall survival (OS) in advanced breast cancer patients with germline BRCA1/2 mutations, long-term results of the phase III EMBRACA trial showed.

With more than 3 years' follow-up, final OS data from the 431-patient study demonstrated that those treated with talazoparib lived a median 19.3 months, as compared to 19.5 months with physician's choice of chemotherapy (HR 0.85, 95% CI 0.67-1.07, P=0.17), reported Jennifer Litton, MD, of MD Anderson Cancer Center in Houston.

But patient-reported outcomes favored talazoparib, a poly-ADP ribose polymerase (PARP) inhibitor, with patients randomized to the drug having significantly improved global health scores from baseline on the EORTC QLQ-30 compared with chemotherapy (2.2 vs -5.7, P=0.001), and a significant delay in time to clinical deterioration (26.3 vs 6.7 months; HR 0.39, 95% CI 0.26-0.56).

"Talazoparib offers a favorable treatment option for patients with locally advanced, metastatic breast cancer and a germline BRCA1/2 mutation," Litton said during her presentation at the American Association for Cancer Research (AACR) virtual meeting. "It is important to note that most patients in this study went on to receive subsequent therapies, which may have confounded the survival analysis."

Based on improvements in progression-free survival (PFS) and objective response rates, EMBRACA led to the 2018 approval of talazoparib for advanced HER2-negative breast cancer patients with germline BRCA1/2 mutations who failed prior treatment. Median PFS for patients on talazoparib was 8.6 months and 5.6 months with physician's choice (HR 0.54, 95% CI 0.41-0.71, P<0.0001).

Following disease progression, most patients in the talazoparib group who went on to subsequent treatments received a platinum chemotherapy (46.3%) and few received an additional PARP inhibitor (<5%). In the physician's choice arm, 41.7% of patients received a platinum agent and 32.6% were treated with a PARP inhibitor.

But sensitivity analyses still showed no significant survival advantage for talazoparib over chemotherapy when investigators adjusted for subsequent PARP inhibitor use (19.3 vs 19.1 months; HR 0.82, 95% bootstrap CI 0.62-1.05) or subsequent PARP inhibitor or platinum therapy use (19.3 vs 17.4 months; HR 0.76, 95% bootstrap CI 0.50-1.03).

An EMBRACA subanalysis presented at AACR by Lida Mina, MD, of Banner MD Anderson Cancer Center in Gilbert, Arizona, explored the impact of tumor BRCA zygosity and genomic loss of heterozygosity (LOH) in the talazoparib arm. LOH had no significant influence on PFS, though high genomic LOH appeared to predict clinical benefit in patients with triple-negative disease (P<0.05).

"At this time, germline BRCA pathogenic variants are the best predictors of PARP inhibitor sensitivity in breast cancer," commented AACR invited discussant Susan Domchek, MD, of the Abramson Cancer Center in Philadelphia. "Not all the tumors are sensitive, but this is true of ER-positive cancer and hormonal therapy, and HER2/neu-positive breast cancer as well."

Domchek added that homologous recombination deficiency scores and genomic LOH "do not seem to add much in those with known germline BRCA1/2 mutations."

From 2013 to 2017, EMBRACA randomized locally advanced or metastatic HER2-negative breast cancer patients with germline BRCA1/2 mutations 2:1 to either oral talazoparib (1 mg daily) or physician's choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine).

Patients in the talazoparib arm tended to be younger (median 45 vs 50 years), had slightly worse performance status, and were more likely to have progressed from their initial diagnosis to advanced breast cancer within 12 months (37.6% vs 29.2%).

Safety was consistent with the primary analysis, with nearly all patients in the trial experiencing an adverse event (AE) of any grade (~98%). For the talazoparib versus chemotherapy arm, respectively, about a third had serious AEs (35% vs 31%), and more than a fourth had grade 3/4 toxicities (28.3% vs 27.0%), though Litton noted that most grade 3/4 AEs in the talazoparib group were manageable hematologic events. Blood transfusions were needed in 39.2% of patients on talazoparib versus 5.6% of those receiving chemotherapy.

One case of acute myeloid leukemia was diagnosed in each arm, and treatment discontinuation for toxicity occurred in 7.7% of patients on talazoparib versus 9.5% of those on chemotherapy.